STRESS RESPONSE IN CELLS AND MICE LACKING GADD34, AN ESSENTIAL COMPONENT OF STRESS-ACTIVATED EIF2¿ PHOSPHATASE

Abstract

ENDOPLASMIC RETICULUM (ER) STRESS PLAYS A KEY ROLE IN CHRONIC HUMAN DISEASES INCLUDING CANCER, DIABETES, HEART DISEASE AND NEURODEGENERATION. IN RESPONSE TO ER STRESS, THE TRANSLATION INITIATION FACTOR, EIF2A, IS RAPIDLY PHOSPHORYLATED BY AN ER TRANSMEMBRANE KINASE, PERK. THIS ATTENUATES GLOBAL PROTEIN SYNTHESIS AND REDUCES THE PROTEIN LOAD, THE SOURCE OF STRESS, IN THE ER. THE PROTEIN ENCODED BY THE GROWTH ARREST AND DNA DAMAGE-INDUCIBLE TRANSCRIPT 34 (GADD34) BINDS PROTEIN PHOSPHATASE 1 AND CATALYZES THE DEPHOSPHORYLATION OF EIF2A, PROMOTING RECOVERY FROM TRANSLATIONAL REPRESSION. TO DATE, GADD34, WHOSE LEVELS ARE TRANSCRIPTIONALLY ELEVATED BY ER STRESS, WAS THOUGHT TO FUNCTION SOLELY IN A NEGATIVE FEEDBACK LOOP THAT PROMOTES CELL RECOVERY FROM STRESS. HOWEVER, WE DISCOVERED THAT GADD34 MRNA WAS CONSTITUTIVELY EXPRESSED AND HIGHLY TRANSLATED IN EARLY STAGES OF ER STRESS. MOREOVER, GADD34 GENERATE A STRESS-ACTIVATED EIF2A PHOSPHATASE WELL BEFORE THE ACTIVATION OF THE GADD34 GENE. OUR